Does Polygenic Risk for Substance-Related Traits Predict Ages of Onset and Progression of Symptoms?

Genetic risk can influence disease progression. We measured the impact of genetic risk for substance use disorders (SUDs) on substance use onset and progression of symptoms DESIGN: Using findings from genome-wide association studies (GWAS) of alcohol use disorder (AUD), opioid use disorder (OUD), and smoking trajectory (SMK) we calculated polygenic risk scores (PRS) in deeply phenotyped independent samples SETTING: Participants were recruited from 2000 through 2020 from U.S. inpatient or outpatient settings or through advertisements PARTICIPANTS: 5,692 European-ancestry individuals (EUR) (56.2% male) and 4,918 African-ancestry individuals (AFR) (54.9% male) MEASUREMENTS: Age of first substance use, regular use, reported problems, and dependence diagnosis, and progression from regular use to onset of problems and dependence for alcohol, opioids, and smoking. We examined the contribution of PRS to each milestone and progression measure FINDINGS: EUR and males reported earlier onset and shorter progression times than AFR and females, respectively. Among EUR, higher AUD PRS predicted earlier onset and more rapid progression to alcohol-related milestones (p<0.001) and although a stronger moderator of problem onset among females (p=0.017), it was more predictive of the progression to problems among males (p=0.005). OUD and SMK PRS in EUR also predicted earlier onset of the respective milestones (p<0.001). Among AFR, where power is lower, AUD PRS predicted age of regular alcohol use (p=0.039) and dependence (p=0.001) and progression from regular use to diagnosis (p=0.045), while SMK PRS predicted earlier age of initiation (p=0.036) CONCLUSIONS: Genetic risk for substance use disorders appears to predict substance use milestones and symptom progression among European-ancestry individuals and, to a lesser extent, African-ancestry individuals.